Arsenical compound.



UTED STATES PA lQQ WALTER. A. JACOBS, OF MOUNT VERNON, AND WADE H. BROWN, MICHAEL HEIDEL- BERGER, AND LOUISE PEARCE, OF NEW YORK, N. Y., ASSIGNORS TO THE ROCKE- IFELLER INSTITUTE FOR MEDICAL RESEARCH, OF NEW YORK, N. Y., A CORPORA- TION OF NEW YORK.

ARSENICAL COMPOUND.

No Drawing.

To all whom it may concern:

Be it known that we, WALTER A. JACOBS, Ph.D., residing at Mount Vernon, Westchester county, New York, VVADE H. BROWN, M. D., residing at Flushing, in the city of New York, borough of Queens, county of Queens, New York, MICHAEL HEIDELBERGER, Pl1.D., residing in the city of New York, borough of Manhattan, county and State of New York, and LOUISE PEARCE, M. D., residing in the city of New York, borough of Manhattan, county and State of New York, all citizens of the United States, have jointly invented a new and Improved Arsenical Compound, of which the following is a specification.

\Ve have found, in the course of our chemical and biological researches, that, whereas the well-known substance chemically designated as N-phenylglycin-p-arsonic acid corresponding to the following formula and described in D. R. P. 204664 .described below into the carboxamid or CONH, group; resulting in a compound which may be designated as N-phenylglycinamid-p-arsonic acid corresponding to the following formula:

r'mcmconn, a remarkable change in the biological prop- Specification of Letters Patent. P t t t, 24, g,

Application filed October 3, 1917. Serial No. 194,459.

increase in the curative power of this new arsenical compound in the treatment of such Infections. We have found in general that substances of this type, which are characterized by the possession of a glycinamid or RNHCH CONH group (R, as seen below, referring to aromatic arsonic acid in general), are powerful therapeutic agents. Thus, we have found that similar results are obtained by the use of the homologues of the above substance, such as the N-tolyglycinamid-p-arsonic acids, and N-xylylglycinamid-p-arsonic acids, and also of the isomers of these substances in which the arsonic acid or AsO H radical is situated in the ortho or meta position to the glycinamid group. We have also found that other compounds belonging to the new type of therapeuticallv valuable arsenicals, are obtained when the glycinamid or aminoacetamid radical is changed to homologues such as the oz-aminopropionamids,

' o As OH l on or the a-aminophenylacetamids,

erties occurs which is shown by the striking both of the hydrogens of the amid group by. an alkyl as shown in the following formulae, where B may be methyl, ethyl, propyl or benzyl or substituted benzyl o \CH CONTLR that this general type of therapeutically important substances was still further extended.

As arsonic acids, all the above-described substances are readily soluble in the equiva lent amounts of alkali or alkali carbonates,

' and when so treated form neutral and stable solutionsof their salts.

Substances of the types above described were obtained in two ways:

1. By the interaction of the corresponding aminophenyl arsonic acid, or preferably its salt, in aqueous or in dilute alcoholic or acetone solution with the corresponding a-halogenacylamid, and when necessary with a hydriodic acid salt, as a catalyzer.

2. By the reaction of the phenylglycin ester arsonic acid with ammonia or an amin, or by any of the other usual methods for converting the COOH group into the CONE group, where R is hydrogen or alkyl.

We shall now describe the preferred n1ethods for the preparation of these substances.

Emample lN-PhenyZgZ 1 cn a m'd-p-airsonic acid.

217 grams of p-aminophenylarsonic acid are dissolved in one liter of normal sodium or potassium hydroxid solution. 187 grains of chloracetamid (or the equivalent amount of bromo or iodo acetamid) are added and the mixture boiled under a reflux for one half to one hour. The clear solution on cooling deposits a copious mass of lustrous crystals of the crude phenylglycinamid-parsonic acid. Concentrated hydrochloric acid is then added until the mixture becomes distinctly acid to Kongo red. The mixture is then filtered and the residue thoroughly washed with cold water. For purification this product is then suspended in several parts of water and sodium hydroxid, or other alkali added until solution is complete. The solution is then filtered and treated with an excess of acetic acid, which precipitates the free acid in pure form. Upon filtering and careful washing and drying of the residue a pure stable product is obtained. In the above reaction the alkaline hydroxid may be substituted by any other suitable basic substance.

This new product with the following formula AS 011 oH H.CH CONH is a colorless crystalline product which, when heated in an open capillary tube, does not melt below 280 (1, and is sparingly soluble in cold water but may be recrystallized from hot Water. It is readily soluble in alkali and alkali carbonate from which it is reprecipitated by acids. Heavy metal salts give insoluble precipitates. It forms stable salts. The sodium salt is recommended for use. This is prepared as fol lows:

One part of the acid is suspended in two parts of water and, while stirring the mixture, sodium hydroxid solution is carefully added until solution of the acid is complete and the reaction ofthe solution is neutral to litmus. Several volumes of 95 per cent. alcohol are then added while stirring the mixture. The sodium salt separates as a colorless lustrous crystalline substance. By filtering the mixture; washing the residue with a little 85 per cent. alcohol and drying it in the air, a stable salt containing approximately one half molecule of water of crystallization is obtained. This salt is extremely soluble in water, forming neutral solutions, and it is therefore especially suitable for therapeutic use. By the substitution of potassium hydroxid or ammonia the corresponding salts can be made by the above process.

Example H.

NH.CH,COOH3 is readily obtainable by the following process:

A mixture of 10 parts phenylvl cinarsonic acid, 30 a t b y p of dry methyl alcohol and 3 parts of concentrated sulfuric acid are boiled under a reflux for two hours. The ester separates as microscopic needles, on cooling the mixture and diluting it With Water. This ester decomposes at about 270 with preliminary softening.

One part of the methyl ester is carefully added to three parts of concentrated ammonia water While the mixture is being stirred and chilled. A thick mass of crystals of the ammonium salt is first obtained which, after a short while, dissolves to a clear solution, as the reaction proceeds. After twentyfour hours the excess ammonia is removed, preferably in vacuo, and the residue diluted with water. An excess of acetic acid is then added, which precipitates the phenylglycinamid-p-arsonic acid in the pure characteristic form described in Example I. In Example 11 the homologous esters, such as the ethyl ester, can be used.

E mample I l IZV (PhenyZ-p-aromlc acid) oa-p henylglycz'n amid.

87 grams of p-aminophenylarsonic acid are dissolved in 400 cc. normal sodium hydroxid solution, and 68 grams phenylchloroacetamid and 500 cc. 95 percent. alcohol are added. To facilitate the reaction 80 grams of sodium iodid are then added and the mixture is heated under a reflux for several hours. On cooling the mixture the reaction product crystallizes out. This, after filtration, is purified by redissolving it in dilute alkali or ammonia and reprecipitating it With acid. For conversion into the sodium salt, this is suspended in a small amount of Water and sodium hydroxid added until solution is complete. This solution, which should be neutral to litmus, is then treated with sodium acetate to salt out the sodium salt. For final purification the salt is recrystallized from 95 per cent. alcohol, from which it separates with approximately 4 molecules of Water of crystallization. The salt is stable and dissolves easily in water.

The foregoing are a few examples of substances falling within the spirit and scope of our invention. It will be obvious to anyone skilled in the art that many variations in the exact constitution of the substances described may be made without departing from the spirit and scope of our invention.

What we claim is:

1. As a new product, an aromatic arsonic acid having in its molecule an a-aminoacylamin side chain, the aromatic nucleus being joined to the a-amino group in'said side chain, the acyl radical of said side chain containing a plurality of carbon atoms.

2. As a new product, an aromatic arsonic acid having in its molecule an a-aminoacylamin side chain having the general v formula -NH.CHR.CONR'R, in' which R is an alkyl or aryl or hydrogen and R and R are alkyl or hydrogen, the aromatic nucleous being joined to the a-amino group in said side chain.

3. As a new'product, an aromatic arsonic acid having in its molecule the glycinamid group NH.CH .CONH attached to the aromatic nucleus as a side chain, the aromatic nucleus being joined to the a-amino group in the said side chain.

4. As a new product, an N-phenylglycinamid arsonic acid.

5. As a new product N-phenylglycin amidp-arsonic acid, having the formula 0 as on IiHCH CONH;

WALTER A. JACOBS, PH. D. WADE H. BROWN, M. D.

MICHAEL HEIDELBERGER, PH. l). LOUISE PEARCE, M. D. 

